Carbovir is a new carbocyclic nucleoside that has potent activity against the HIY in vitro. The compound has been selected by the NIH for Development as a promising drug for AIDS. We have recently developed an HPLC assay For carbovir and have studied the pharmacokinetics of carbovir after oral and intravenous administrations to rats. The bioavaibility if carbovir was on)y 11.7+4.7%. To improve the oral absorption of carbovir. we propose to synthesize and evaluate several classes of carbovir prodrugs. A second major goal of a prodrug strategy is to increase penetration into the CNS. AIDS patients have many reurologicai problems that may be directly due to an HIV brain infection. Four classes of prodrugs will be synthesized: 1) Several 5'-0H esters; 2) Lipophilic carbovir monophosphate esters (carbovir-diphosphate- L-dipalmitin) and bis(acyloxymethyl) esters of carbovir- morphosphate: 3a.) 6-amino-carbovir (adenosine deaminase activated), 3b.) 6-deoxy-carbovir(xanthine oxidase activated 4) Dihydropyridine/ pyridinium esters for selective CNS uptake. Systematic aviator will be done to the follow) experiments: 1) In vitro metabolism with serum, liver, brain, or intestinal enzyme preparations. 2) Determination of the bioavaibility of selected Prodrugs compared to carbovir tn animals. 3) Examination of CNS peretratical if carbovir and its prodrugs. 4) Determination of the site of pre-systemic metabolism of the prodrugs with an intestinal- liver perfusion model system. The methods developed for carbovir prodrugs may also be used with other promising antiviral nucleosides.